Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Australia.
Metabolism and Inflammation Program, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
Diabetes Obes Metab. 2017 Jul;19(7):936-943. doi: 10.1111/dom.12896. Epub 2017 Mar 3.
To determine the effect of Scriptaid, a compound that can replicate aspects of the exercise adaptive response through disruption of the class IIa histone deacetylase (HDAC) corepressor complex, on muscle insulin action in obesity.
Diet-induced obese mice were administered Scriptaid (1 mg/kg) via daily intraperitoneal injection for 4 weeks. Whole-body and skeletal muscle metabolic phenotyping of mice was performed, in addition to echocardiography, to assess cardiac morphology and function.
Scriptaid treatment had no effect on body weight or composition, but did increase energy expenditure, supported by increased lipid oxidation, while food intake was also increased. Scriptaid enhanced the expression of oxidative genes and proteins, increased fatty acid oxidation and reduced triglycerides and diacylglycerides in skeletal muscle. Furthermore, ex vivo insulin-stimulated glucose uptake by skeletal muscle was enhanced. Surprisingly, heart weight was reduced in Scriptaid-treated mice and was associated with enhanced expression of genes involved in oxidative metabolism in the heart. Scriptaid also improved indices of both diastolic and systolic cardiac function.
These data show that pharmacological targeting of the class IIa HDAC corepressor complex with Scriptaid could be used to enhance muscle insulin action and cardiac function in obesity.
确定 Scriptaid（一种通过破坏 IIa 类组蛋白去乙酰化酶（HDAC）核心抑制复合物来复制运动适应性反应的化合物）对肥胖症中肌肉胰岛素作用的影响。
通过每日腹腔内注射，将饮食诱导肥胖的小鼠给予 Scriptaid（1mg/kg），持续 4 周。对小鼠进行全身和骨骼肌代谢表型分析，以及超声心动图检查，以评估心脏形态和功能。
Scriptaid 治疗对体重或组成没有影响，但确实增加了能量消耗，这得益于脂质氧化的增加，同时也增加了食物摄入。Scriptaid 增强了氧化基因和蛋白质的表达，增加了脂肪酸氧化，减少了骨骼肌中的甘油三酯和二酰基甘油。此外，体外胰岛素刺激的骨骼肌葡萄糖摄取也得到增强。令人惊讶的是，Scriptaid 治疗的小鼠心脏重量减轻，并且与心脏中涉及氧化代谢的基因表达增强有关。Scriptaid 还改善了舒张和收缩性功能的指标。
这些数据表明，用 Scriptaid 靶向 IIa 类 HDAC 核心抑制复合物进行药理学治疗可能用于增强肥胖症中肌肉胰岛素作用和心脏功能。
